This invention is directed to the field of pharmaceutical compounds and methods of use. In particular, this invention is directed to analogs of the di-peptide, L-Glu-L-Trp in which the nitrogen of the indole ring of tryptophan is substituted with a carbon. These analogs have similar immunomodulating and anti-angiogenic activity to the parent compound.
L-Glu-L-Trp, also known as thymogen, is a dipeptide known normalize immune system function. The drug was found to be the active principle in an extract of the thymus gland called thymosin. (Morozov et al., U.S. Pat. No. 5,070,076.) The dipeptide has been shown to be effective in the treatment of immunodeficient, immunodepressed or hyperactive immune states. (Khavinson et al., WO 92/17191; Khavinson et al., WO 95/03067; and Morozov et al., U.S. Pat. No. 5,538,951.) Pro-drugs of L-Glu-L-Trp, such as cyclized versions of the dipeptide or linear polymers of the dipeptide, are processed by the body into the active compound. (Khavinson et al., WO 93/08815.) Two related compounds, L-Ile-L-Trp and L-Leu-L-Trp, also have been shown to have immunomodulating properties similar to L-Glu-L-Trp. (Khavinson et al., WO 94/20063.) In addition to these properties, L-Glu-L-Trp has anti-angiogenic activity. (Green et al., WO 97/12625.)
Other related compound reported to stimulate the immune response are the tripeptide Pyr-Leu-Trp and phoshoramidon (sugar-Leu-Trp). (Polita et al., U.S. Pat. No. 5,143,903.) However, there is no report of these compounds being tested against HIV infection.
These tryptophan-containing dipeptides are believed to function, at least in part, by reversibly associating with specific cellular receptors, namely "CD2" receptors, thereby inducing conformation changes in the receptor which "trigger" intracellular mechanisms resulting in up-regulation of adenylate cyclase and an increase in AMP. They simultaneously increase the affinity of the CD2 receptor for its "target" ligand. This increase in affinity is believed to heighten the interaction between these cells and their natural ligands, thereby facilitating such interaction and encouraging cellular response to such interaction. (Khavinson et al., WO 94/20063.)
This application is related to U.S. Pat. No. 5,538,951 and to U.S. application Ser. Nos. 08/452,411, filed May 26, 1995 (issued as U.S. Pat. No. 5,728,680) and 08/415,009, filed Mar. 31, 1995 (issued as U.S. Pat. No. 5,789,384).